Xanthene and thioxanthene derivatives

ABSTRACT

The present invention relates to novel thioxanthene and xanthene derivatives which have useful pharmacodynamic activity, such as neuroleptic activity and antiemetic activity, methods for the preparation of said derivatives, pharmaceutical compositions containing same, and a method for the treatment of psychic disorders by administering a therapeutically active amount of one of said derivatives to a living animal body, including human beings. The new compounds of the present invention corresponds to the Formula I: &lt;IMAGE&gt; I   wherein X is a halogen atom, an alkyl group with from one to four carbon atoms inclusive, an alkyloxy group with from one to four carbon atoms inclusive, a methylthio group, a methylsulphonyl group, a dimethylsulfamoyl group, a trifluoromethyl group or an acetyl group; Y is hydrogen, fluorine or a methyl group; Z is oxygen or sulphur; n is an integer from zero to three inclusive, and R is a cycloalkyl group with from four to six carbon atoms inclusive in the ring substituted with from one to four substituents selected from optionally esterified hydroxy- or hydroxymethyl groups, methyl groups, amino groups, acetamido groups, mesylamino groups or oxo groups, a five- or six-membered saturated heterocyclic ring having one or two heteroatoms selected from oxygen and nitrogen atoms and being optionally substituted with an optionally esterified hydroxy group or oxo group, any esterified hydroxy group present being an ester of an aliphatic carboxylic acid having from ten to twentytwo carbon atoms inclusive, as well as their non-toxic pharmaceutically acceptable acid addition salts.

This is a division of application Ser. No. 035,735, filed May 3, 1979.

BACKGROUND OF THE INVENTION

In the past, several drugs having a tricyclic structure have been founduseful in the treatment of severe psychotic disorders, especially of theschizophrenic type. Some of these drugs are thioxanthenes which aresubstituted in the 2-position of one of the benzene rings, and some ofthe most active are described in U.S. Pat. No. 3,116,291. Recently somethioxanthenes having a fluoro atom in the 6-position have beendescribed, for example in U.S. Pat. No. 4,042,695 as having neurolepticproperties of the same level as the known thioxanthene-neuroleptics buta much lower level of pharmacological effects associated withextrapyrimidal symptoms. Further, some piperidylidene-thioxanthenederivatives having almost no extrapyrimidal side effects have beendescribed in Belgian Pat. No. 835,224. However, the said knownthioxanthene compounds which have the lowest extrapyrimidal side effectsalso have relatively short-acting neuroleptic effects.

SUMMARY OF THE INVENTION

According to the present invention it has now surprisingly been foundthat the compounds of Formula I as well as their non-toxic acid additionsalts have both strong and very long-lasting neuroleptic effects and, atthe same time, a pharmacological profile which indicates relatively lowextrapyrimidal side effects when they are evaluated according tostandard reliable published test methods. They also have a low acutetoxicity compared with related thioxanthene derivatives, which makes thetherapeutic index favorable. Moreover, they have moderately stronganticholinergic effects, and comparatively low undesired sedativeeffect.

This invention also includes pharmaceutically acceptable salts of thecompounds of Formula I formed with non-toxic organic acids. Such saltsare easily prepared by methods known to the art. The base is reactedwith either the calculated amount of organic or inorganic acid in anaqueous miscible solvent, such as acetone or ethanol, with isolation ofthe salt by concentration and cooling or an excess of the acid inaqueous immiscible solvent, such as ethyl ether or chloroform, with thedesired salt separating directly. Exemplary of such organic salts arethose with maleic, fumaric, benzoic, ascorbic, embonic, succinic,oxalic, bis methylene-salicylic, methanesulfonic, ethanedisulfonic,acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophyllineacetic acids as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids. Of course, these salts may also be prepared by the classicalmethod of double decomposition of appropriate salts, which is wellknownto the art.

The compounds of Formula I may exist in form of isomers of the cis-transtype, and the present invention comprises the single isomers as well asmixtures of the isomers. The novel xanthene and thioxanthene derivativesof the invention may be administered both orally and parenterally, forexample in the form of tablets, capsules, powders, syrups, suppositoriesor solutions or suspensions for injection.

The invention moreover relates to a method for the preparation of thenovel compounds of Formula I, which comprises (a) reacting a compound ofthe following formula: ##STR2## wherein X, Y and Z are as defined abovewith a reactive ester of a compound of the formula

    HO.(CH.sub.2).sub.n.R

wherein n and R are as above defined and any hydroxy or amino grouppresent is protected by esterification, or

(b) reducing a compound of the formula: ##STR3## wherein Y and Z are asdefined above, R₁ is as R except that it has no oxo-group and anyhydroxy group is protected, X₁ is a halogen atom, an alkyl group withfrom one to four carbon atoms inclusive, an alkyloxy group with from oneto four carbon atoms inclusive, a methylmercapto group or atrifluoromethyl group; and "m" is an integer from zero to two, withlithium aluminium hydride, or

(c) reducing a compound of the formula: ##STR4## wherein X₁, Z and Y areas defined above, and U is --COOH or --OOC.phenyl with lithium aluminiumhydride in order to obtain a compound of the formula: ##STR5## whereinX₁, Z and Y are as defined above and U₁ is --CH₂ OH or --OHrespectively, or

(d) reducing a compound of the formula: ##STR6## wherein X₁ and Y are asdefined above with lithium aluminium hydride in order to obtain acompound of the formula: ##STR7## or

(g) oxidizing a compound of the formula: ##STR8## wherein X₁, Z, Y and nare as defined above, by means of a ketone in the presence of analuminum alkoxide, in order to obtain a compound of Formula I, wherein Ris a cyclohexanone group, whereupon the compound of Formula I obtainedis isolated, and any hydroxy group present optionally esterified with areactive derivative of an aliphatic carboxylic acid having from ten totwenty-two carbon atoms inclusive and, if desired, acetylating ormesylating any amino group present in wellknown manner, as the free baseor a non-toxic acid addition salt thereof.

Several of the intermediates of Formula II and all the intermediates ofFormula III-VII are novel compounds and fall within the scope of thepresent invention.

The intermediates of Formula II may conveniently be prepared accordingto the following reaction scheme: ##STR9## except that X may not be anacetyl group.

When preparing compounds of Formula II wherein X is acetyl they mayconveniently be prepared as described in Belgian Pat. No. 558,171according to the following scheme ##STR10## the further processing beingas described above.

The intermediates of Formula III may conveniently be prepared in thefollowing way:

    II+Cl OC (HC.sub.2).sub.m.R.sub.1 →                 III

any protecting group being removed before reduction with lithiumaluminum hydride.

Any other obvious chemically equivalent method for the preparation ofthe amides of Formula III may of course be used.

The intermediates of Formula III may also be prepared in the followingway: ##STR11##

The intermediates of Formula IV may according to the invention beprepared by a reductive alkylation of compounds of Formula II withcompounds of the formula: ##STR12## wherein U is as defined above bymeans of sodium cyanoboron hydride (NaCNBH₃).

The intermediates of Formula V, where --COOH is in ortoposition, mayaccording to the invention be prepared by reacting a compound of FormulaII with 1,2-cyclohexanedicaboxylic acid anhydride.

Some of the xanthones and thioxanthones used as starting materials forthe preparation of the intermediates of Formula II are known substances,the preparation of which is described for example in U.S. Pat. Nos.3,116,291 and 4,042,695 and Belgian Pat. No. 558,171. Others are new butthey are prepared by methods known in the art for the preparation ofsimilar substances.

In method (a) the reactive esters of the compounds of formulaHO.(CH₂)_(n).R may according to the invention conveniently be esters ofhydrogen halide, such as hydrogen chloride or hydrogen bromide, oresters of organic sulphonic acids, such as methane sulphonic acid,ethane sulphonic acid, p-toluene sulphonic acid or the like. Otherwise,the reaction (a) is a wellknown reaction type, which is normally carriedout in inert organic solvents and under basic conditions in order toneutralize the acid formed by the reaction.

The reductions according to methods (b), (c) or (e) may according to theinvention conveniently be carried out by lithium aluminium hydride orsimilar reducing agents which will not at the same time reduce thedouble bond between the thiaxanthene and piperidine rings.

The oxidation according to method (g) of the invention is a socalledOppenauer Oxidation and may according to the invention be carried out inthe presence of an excess of a ketone (preferably cyclohexanone oracetone), in the presence of an aluminium alkoxide (preferablyaluminiumisopropoxide).

The optional esterification of any hydroxy group or groups present inthe compound of Formula I may according to the invention conveniently becarried out by a reactive derivative of the carboxylic acid having fromten to twenty-two carbon atoms inclusive, such as an acid chloride oranhydride. As carboxylic acids may be mentioned decanoic acid, palmiticacid and behenic acid.

The optional acetylation or mesylation of any amono group present in acompound of Formula I may be carried out in conventional manner bytreatment with acetic anhydride, acetylchloride or mesylchloride.

The methods of the invention shall in the following be illustrated bysome examples which may not be construed as limiting:

EXAMPLE 1 Preparation of the starting compounds of Formula II:4-(2-trifluoromethyl-6-fluoro-9-hydroxy-9-thioxanthenyl)-1-methylpiperidine.

In a 3 liter three necked flask equipped with stirrer, reflux condenserand separatory funnel were placed 60 grams of magnesium filings, 1.5liter of dry tetrahydrofuran and a few crystals of iodine, whereupon 1milliliter of ethylene bromide was added and the mixture warmed untilthe reaction starts. After the reaction has been completed 300 grams offreshly distilled 4-chloro-1-methylpiperidine were added while stirringat a rate which makes the reaction mixture boil by the heat of reaction.After the addition has been completed the reaction mixture was heatedunder reflux for three hours. Thereafter the reaction mixture was cooledin an ice bath and 430 grams of 2-trifluoro-acetyl-6-fluoro-9-thioxanthone (preparation described in U.S. Pat. No.4,042,695) were added portion-wise while stirring and keeping thetemperature at 10-20 degrees Centigrade. Thereafter the reaction mixturewas stirred without cooling for 30 minutes. The dark coloured reactionmixture was poured onto crushed ice, acetic acid was added until themagnesium hydroxide precipitated had been dissolved, and the aqueousphase washed with 4 liters of ether. The organic phase was extractedtwice with 1 liter of 10% acetic acid. The combined aqueous phase wasmade basic with aqueous ammonia and the base which separated out wasextracted with ether. The ether extract was dried over anhydrouspotassiumcarbonate, treated with active carbon and evaporated to avolume of about one liter. By cooling and standing 385 grams of4-(2-trifluoromethyl-6-fluoro-9-hydroxy-9-thioxanthenyl)-1-methyl-piperidinewere obtained as white crystals which melted at 250-255 degreesCentigrade.

In corresponding manner the xanthenols and thioxanthenols of thisformula were prepared:

    ______________________________________                                         ##STR13##                                                                                                   MP in degrees                                  X             Y        Z       Centigrade                                     ______________________________________                                        2-CF.sub.3    H        S       240-242                                        2-Cl          H        S       200-205                                        2-Cl          F        S       225-230                                        2-SCH.sub.3   H        S       190-195                                        2-SCH.sub.3   F        S       180-189                                        3-F           H        S       195-198                                        3-F           F        S       210-211                                        2-CH.sub.3    F        S       200-220                                        2-F           CH.sub.3 S       178-180                                        2-SO.sub.2 N(CH.sub.3).sub.2                                                                F        S       210-220                                        2-SO.sub.2 CH.sub.3                                                                         H        S       252-260                                        2-OCH.sub.3   F        S       183-185                                        2-CF.sub.3    CH.sub.3 S       235-238                                         ##STR14##    H        S       206-208                                        2-OCH.sub.3   H        S       175-177                                        2-SCH.sub.3   F        O       164-166                                        2-Cl          H        O       205-210                                        ______________________________________                                         4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-1-methyl-piperidine. 

100 grams of4-(2-trifluoromethyl-6-fluoro-9-hydroxy-9-thioxanthenyl)-1-methylpiperidine were disssolved in a mixture of 500 milliliters of glacialacetic acid and 300 milliliters of concentrated hydrochloric acid. Thereaction mixture was heated under reflux for 21/2 hour, whereupon themajor part of the acid mixture was distilled off and the residue pouredinto ice water. The aqueous solution was made basic with aqueous ammoniaand extracted with ether. The ether phase was dried over anhydrouspotassium carbonate, treated with active carbon and evaporated to about300 milliliters. Upon cooling and standing 76 grams of4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-1-methyl-piperidinewere obtained as white crystals which melted at 100-102 degreesCentigrade.

In corresponding manner were prepared the compounds of the followingformula:

    ______________________________________                                         ##STR15##                                                                                                   MP in degrees                                  X             Y        Z       Centigrade                                     ______________________________________                                        2-CF.sub.3    H        S       100-102                                        2-Cl          H        S       Oil                                            2-Cl          F        S       130-132                                        2-SCH.sub.3   H        S       104-106                                        2-SCH.sub.3   F        S       114-117                                        3-F           H        S       115-117                                        3-F           F        S       138-140                                        2-CH.sub.3    F        S       90-92                                          2-F           CH.sub.3 S       93-96                                          2-SO.sub.2 N(CH.sub.3).sub.2                                                                F        S       160-162                                        2-SO.sub.2 CH.sub.3                                                                         H        S       162-166                                        2-OCH.sub.3   F        S       125-127                                        2-CF.sub.3    CH.sub.3 S       157-160                                        2-COCH.sub.3  H        S       125-127                                        2-OCH.sub.3   H        S       102-104                                        2-SCH.sub.3   F        O       134-136                                        2-Cl          H        O       Oil                                            ______________________________________                                    

The compound 4-(2-acetyl-9-thioxanthenylidene)-1-methylpiperidine, wasprepared in the following way:

140 grams of the ethylene glycal ketal of2-acetyl-9-(1-methyl-4-piperidyl)-9-thioxanthenol (MP 206-208 degreesCentigrade) were heated for two hours under reflux with a mixture of1500 milliliters of propionic acid and 100 grams of 2-sulfobenzoic acidanhydride. Thereafter the mixture was evaporated in vacuum, the residuedissolved in water and made alkaline. The base which separated out wasextracted with ether, the ether phase dried over anhydrous potassiumcarbonate and evaporated until beginning crystallization. The crystalswere sucked off and dried. - 50 grams of4-(2-acetyl-9-thioxanthenylidene)-1-methyl-piperidine were obtainedmelting at 125-127 degrees Centigrade.

1-(2,2,2-trichloroethoxycarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine

A mixture of 150 grams of4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-1-methylpiperidine,100 grams of the 2,2,2-trichloroethylester of chloroformic acid and 1liter of dry benzene were heated under reflux for 16 hours. Aftercooling the benzene solution was washed with dilute hydrochloric acidand dilute sodium hydroxide solution, dried over anhydrous potassiumcarbonate, filtered and evaporated in vacuum. Thereby somewhat impure1-(2,2,2-trichloroethoxycarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinewas obtained as an yellow oil which was used in the next step withoutfurther purification. Yield: 219 grams.

4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine

The oil from the previous step was dissolved in 2.5 liters of 90%aqueous acetic acid; the solution was cooled to below 10 degreesCentrigrade and while stirring were added 290 grams of zink which justbefore had been washed with dilute hydrochloric acid, dilute sodiumhydroxide solution, water, ethanol and ether. The temperature rises bythe heat of reaction to 15-20 degrees Centrigrade. After 15 minutes theice bath was removed and the stirring continued for further 3 hours.During this stage the temperature rised to 25-30 degrees Centigrade.

Thereafter the reaction mixture was filtered, washed with 90% aqueousacetic acid, evaporated in vacuum; water was added to the residue andaqueous ammonia added until basic reaction. The base which separated outwas extracted with ether, the ether extract dried over anhydrouspotassium carbonate and filtered. After evaporation the residue wascrystalllized from ether-petroleum ether (1:1). 116 grams of4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine wereobtained as white crystals which melted at 125-130 degrees Centigrade.

In corresponding manner were prepared the following starting materialsof Formula II

    ______________________________________                                         ##STR16##                    II                                              X           Y       Z      MP in degrees Centigrade                           ______________________________________                                        2-CF.sub.3  H       S      116-118                                            2-Cl        H       S      137-140                                            2-Cl        F       S      135-136                                            2-S . CH.sub.3                                                                            H       S      130-131                                            2-S . CH.sub.3                                                                            F       S      128-132                                            3-F         H       S      126-128                                            3-F         F       S      148-150                                            2-CH.sub.3  F       S      122-126                                            2-F         CH.sub.3                                                                              S      125-127                                            2-SO.sub.2 N(CH.sub.3).sub.2                                                              F       S      196-198                                            2-SO.sub.2 CH.sub.3                                                                       H       S      140-180 (amorph.)                                  2-OCH.sub.3 F       S      130-135                                            2-CF.sub.3  CH.sub.3                                                                              S      135-137                                            2-CO . CH.sub.3                                                                           H       S      115-117                                            2-OCH.sub.3 H       S      122-124                                            2-S . CH.sub.3                                                                            F       O      118-128                                            2-Cl        H       O      140-145                                            ______________________________________                                    

EXAMPLE 2 (Method b))1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine

In a separatory funnel were placed a solution of 23 grams of4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine in 100milliliters of toluene and a solution of 15 grams of potassium carbonatein 100 milliliters of ice water, whereupontrans-4-acetoxycyclohexanecarbonyl chloride prepared from 13 grams ofcorresponding acid (Helv.Chim.Acta 27, 793-800, 1944) was added and themixture was shaken for 5 minutes. The aqueous phase was separated anddiscarded and the organic layer washed with dilute hydrochloric acid,dried over anhydrous potassium carbonate, filtered and evaporated invacuum. The residue which consisted of somewhat impure1-(trans-4-acetoxycyclohexanecarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinewas used without further purification in the reduction process and wasdissolved in dry ether and added dropwise to a solution of 4 grams oflithiumaluminium hydride in dry ether. The reaction mixture was heatedunder reflux for 3 hours. Water was added with caution until theprecipitate clotted. The ether phase was decanted, the precipitatewashed thoroughly with ether, and the combined etherphases dried overanhydrous potassium carbonate, treated with active carbon and filtered.The major part of the ether was distilled off and 100 milliliters ofpetroleum ether were added. Upon cooling and standing 21 grams of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidinewere obtained as a white crystalline substance melting at 144-146degrees Centigrade.

In corresponding manner was prepared:

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperidine,MP: 185-190 degrees Centigrade.

1-(trans-2-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperidine, MP: 96-103 degrees Centigrade.

1-(cis-4-hydroxymethylcyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperidine,MP: 85-90 degrees Centigrade.

1-(5-hydroxy-1,3-dioxan-2-yl)methyl-4-(2-chloro-9-thioxanthenylidene)-piperidine,MP: 160-162 degrees Centigrade.

1-(3,4-dihydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperidine,MP: 173-180 degrees Centigrade.

1-(trans-3-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidineoxalate, MP: 155-157 degrees Centigrade.

1-(4-hydroxy-4-methylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 80-90 degrees Centigrade.

1-(cis-2-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 85-90 degrees Centigrade.

1-(3-trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine,amorphous substance.

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 138-144 degrees Centigrade.

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-9-thioxanthenylidene)-piperidine,hydrochloride. MP: 285-287 degrees Centigrade.

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 178-180 degrees Centigrade.

1-(3-trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-chloro-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 110-120 degrees Centigrade.

1-(trans-4-hydroxycyclohexylmethyl)-4-(3,6-di-fluoro-9-thioxanthenylidene)-piperidine,MP: 154-156 degrees Centigrade.

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-fluoro-6-methyl-9-thioxanthenylidene)-piperidine,MP: 158-162 degrees Centigrade.

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-methyl-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 181-185 degrees Centigrade.

1-(5-hydroxy-1,3-dioxan-2-yl)methyl-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 138-140 degrees Centigrade.

1-(5-hydroxy-1,3-dioxan-2-yl)methyl-4-(2-methylthio-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 129-131 degrees Centigrade.

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-methoxy-6-fluoro-9-thioxanthenylidene)-piperidine,MP: 138-142 degrees Centigrade.

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-methyl-9-thioxanthenylidene)-piperidine,MP: 145-147 degrees Centigrade.

EXAMPLE 31-(Cis-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperidine(Method (a))

The starting material, cis-(1-mesyloxymethyl-4-hydroxy)cyclohexane, wasprepared in the following way:

24 Grams of cis-4-hydroxycyclohexanemethanol were dissolved in a mixtureof 70 milliliters of dry pyridine and 100 milliliters of chloroform. Ata temperature of -20 degrees Centigrade were added 23 grams of mesylchloride dropwise while stirring. The mixture was kept at -10 to -20degrees Centigrade for 2 hours while stirring, whereupon the mixture wasleft standing over night at room temperature. The reaction mixture wasthen poured into ice-water, the chloroform layer was separated off andwashed with dilute hydrochloric acid. The chloroform phase was thendried over anhydrous magnesium sulphate, filtered and evaporated. Theresidue was distilled in vacuum and 30 grams ofcis-(1-mesyloxymethyl-4-hydroxy)cyclohexane were obtained as an oilboiling at 120-125 degrees Centigrade/1 mm Hg.

A mixture of 6 grams of 4-(2-chloro-9-thioxanthenylidene)piperidine, 4grams of cis-(1-mesyloxymethyl-4-hydroxy)cyclohexane, 1.5 grams offinely crushed potassium carbonate and 25 milliliters ofmethylisobutylketone was heated under reflux for 5 hours while stirring.After cooling were added 200 milliliters of ether, and the organic phasewas extracted with 5% aqueous methane sulphonic acid. The aqueous phasewas made alkaline with aqueous ammonia, and the base which precipitatedwas extracted with ether. The etherphase was dried over anhydrouspotassium carbonate, treated with active carbon and evaporated. Theresidue was crystallized from cyclohexane. Yield: 1.5 grams of1-(cis-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperidine,which melted at 100-103 degrees Centigrade.

In corresponding manner were prepared:

1-(2-(2-Oxazolidinone-3-yl)ethyl)-4-(2-chloro-9-thioxanthenylidene)piperidine,HCl. MP: 250-252 degrees Centigrade.

1-(5-hydroxy-1,3-dioxan-2-yl)methyl-4-(2-chloro-9-thioxanthenylidene)piperidine.MP: 160-162 degrees Centigrade.

1-(3-trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperidine.MP: 173-180 degrees Centigrade.

1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 144-146 degrees Centigrade.

1-(cis-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 149-152 degrees Centigrade.

1-(trans-3-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidineoxalate. MP: 155-157 degrees Centigrade.

1-(4-hydroxy-4-methylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 80-90 degrees Centigrade.

1-(2-cis-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 85-90 degrees Centigrade.

1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.Amorphous substance.

1-(1,3-Dioxan-4-ylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 151-153 degrees Centigrade.

1-(4-tetrahydropyranylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidineoxalate. MP: 138-140 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-thioxanthenylidene)piperidine.MP: 138-144 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-9-thioxanthenylidene)piperidine,HCl. MP: 285-287 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-6-fluoro-9-thioxanthenylidene)piperidine.MP: 178-180 degrees Centigrade.

1-(2-(2-Oxazolidinon-3-yl)ethyl)-4-(2-chloro-6-fluoro-9-thioxanthenylidene)piperidine,HCl. MP: 248-250 degrees Centigrade.

1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-chloro-6-fluoro-9-thioxanthenylidene)piperidine.MP: 110-120 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(3,6-difluoro-9-thioxanthenylidene)-piperidine.MP: 154-156 degrees Centigrade.

1-(2-Oxazolidinon-3-yl)ethyl)-4-(2-fluoro-6-methyl-9-thioxanthenylidene)-piperidine,HCl. MP: 243-246 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-fluoro-6-methyl-9-thioxanthenylidene)-piperidine.MP: 158-162 degrees Centigrade.

1-(2-(2-Oxazolidinon-3-yl)ethyl)-4-(2-methyl-6-fluoro-9-thioxanthenylidene)-piperidine,HCl. MP: 252-254 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methyl-6-fluoro-9-thioxanthenylidene)-piperidine.MP: 181-185 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-bromo-6-fluoro-9-thioxanthenylidene)-piperidine.

1-(4-hydroxymethylcyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 196-199 degrees Centigrade.

1-(4-hydroxycyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine,HCl. MP: 208-211 degrees Centigrade.

1-(2-Dioxolylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 137-139 degrees Centigrade.

1-Morpholinoethyl-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine,2HCl. MP: 300-305 degrees Centigrade.

1-(Cis-2-hydroxymethylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 85-100 degrees Centigrade.

1-(3-Tetrahydrofurylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidineoxalate. MP: 191-192 degrees Centigrade.

1-(2-(Cis-4-hydroxycyclohexyl)ethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinemaleate. MP: 147-150 degrees Centigrade.

1-(1-Methyl-4-piperidylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine,2HCl. MP: 322-324 degrees Centigrade.

1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-bromo-9-thioxanthenylidene)piperidineoxalate. MP: 184-188 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-dimethylsulfamoyl-6-fluoro-9-thioxanthenylidene)piperidine,MP: 110-120 degrees Centigrade (amorph.)

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methylsulfonyl-9-thioxanthenylidene)piperidine,MP: 70-85 degrees Centigrade (amorph.)

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-acetyl-9-thioxanthenylidene)piperidineoxalate hydrate, MP: 140-210 degrees Centigrade.

1-(2-(2-Imidazolidone-1-yl)ethyl)-4-(2-chloro-9-thioxanthenylidene)piperidine,MP: 205-206 degrees Centigrade.

1-(2-(2-Imidazolidone-1-yl)ethyl-4-(2-methylthio-6-fluoro-9-thioxanthenylidene)piperidinemonohydrate, MP: 126-132 degrees Centigrade.

1-(1,3,4,5-tetrahydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-thioxanthenylidene)piperidine,MP: 90-100 degrees Centigrade (amorph.)

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-xanthenylidene)piperidinehydrate, MP: 122-126 degrees Centigrade.

1-(Trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-xanthenylidene)piperidine

EXAMPLE 41-(Cis-4-hydroxycyclohexylethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidineand maleate (Method b)

7.3 Grams of4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine weredissolved in 50 milliliters of dry methylene chloride. Then 3.8 grams ofcis-4-hydroxycyclohexane acetic cid (J.Am.Ch.Soc. 70, pg. 1898-99(1948)) and 5 grams of dicyclohexylcarbodiimide were added. The mixturewas heated at temperatures from 22 to 30 degrees Centigrade during whichthe dicyclohexylurea formed separated out and was then left standingovernight. The precipitate was filtered from the solution which was thenevaporated, and the residue was dissolved in ether. The solution waswashed with dilute hydrochloric acid, dried over anhydrous potassiumcarbonate, filtered and evaporated. The residue, which was an oil, waddried by evaporation in vacuum with toluene and consisted of somewhatimpure1-(cis-4-hydroxycyclohexylmethylcarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinewhich was used without further purification in the next step. The oilwas dissolved in dry ether, and 2 grams of lithium aluminum hydride wereadded in small portions. The mixture was heated under reflux for onehour. Then water was added dropwise until the precipitate formedclotted. The ether phase was decanted, the precipitate washed thoroughlywith ether, the combined ether phases were dried over anhydrouspotassium carbonate and treated with active carbon and filtered. Theether was evaporated, and1-(cis-4-hydroxycyclohexylethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinewas obtained as a yellow oil.

Following solution in acetone and addition of maleic acid 8 grams of themaleate were obtained as white crystals which melted at 147-150 degreesCentigrade.

In corresponding manner were prepared:

1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-methoxy-9-thioxanthenylidene)piperidineoxalate. MP: 235-236 degrees Centigrade.

1-(3,4,5-Cis-trihydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro9-thioxanthenylidene)piperidineoxalate. MP: 172-175 degrees Centigrade.

1-(3,4,5-Cis-trihydroxycyclohexylmethyl)-4-(2-methylthio-6-fluoro-9-thioxanthenylidene)piperidinehydrate. MP: 115-120 degrees Centigrade.

1-(3-Trans-4-cis-dihydroxycyclohexylmethyl)-4-(2-chloro-9-xanthenylidene)piperidine.

EXAMPLE 51-(Trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine

The starting material,1-(4-cyclohexanone-carbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine,was obtained in the following way:

25 Grams of4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine weredissolved in 200 milliliters of dry methylene chloride. To this solutionwere added 12 grams of 4-cyclohexanone carboxylic acid and 16 grams ofdicyclohexylcarbodiimide, whereby temperature in the reaction rose from20 to 32 degrees Centigrade under simultaneous separation ofdicyclohexylurea. The resulting mixture was then treated in the samemanner as described in Example 4. The resulting1-(4-cyclohexanonecarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidinewas obtained by crystallization from isopropyl ether and melted at165-179 degrees Centigrade. Yield: 15 grams.

5 Grams of this amide were dissolved in dry ether and reduced with onegram of lithium aluminum hydride as described in Example 2, and thereaction mixture worked up as described there. 3.5 Grams of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinewere obtained as a white crystalline substance which melted at 144-146degrees Centigrade.

EXAMPLE 61-(4-Hydroxy-4-methylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine(Method d)

14 Grams of1-(4-cyclohexanonecarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine,obtained as described in Example 5, were dissolved in a mixture of 50milliliters of dry tetrahydrofuran and 150 milliliters of dry ether. At5-10 degrees Centigrade was added dropwise and while stirring a solutionof methyl magnesium iodide in ether prepared from 6 grams of methyliodide. Thereafter the reaction mixture was poured unto crushed ice, andthe magnesium hydroxide which precipitated was dissolved by addition ofdilute hydrochloric acid. The ether phase was washed once with dilutehydrochloric acid, dried over anhydrous potassium carbonate, filteredand evaporated. The resulting oil was reduced with 3 grams of lithiumaluminium hydride without further purification as described in Example2. The base formed by the reduction was purified by solution in 5%aqueous methane sulphonic acid, the solution washed with ether and thebase precipitated with dilute aqueous ammonia. The base was extractedwith ether, the ether phase dried over anhydrous potassium carbonate,treated with active carbon and evaporated, finally in vacuum. 12 Gramsof1-(4-hydroxy-4-methylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinewere thereby obtained as an almost white amorphous substance whichmelted at 80-90 degrees Centigrade.

EXAMPLE 71-(4-Hydroxymethylcyclohexyl)-4-(2-trifluoromethyl-9-thioxanthenylidene)-piperidine(Method d)

The starting material, the methyl ester of1-(4-carboxycyclohexyl)-4-(2-trifluoromethyl-9-thioxanthenylidene)piperidine,was obtained in the following way:

11.6 Grams of 4-(2-trifluoromethyl-9-thioxanthenylidene)piperidine weredissolved in 30 milliliters of dry methanol, and to the solution wereadded 5.5 grams of 4-cyclohexanonecarboxylic acid and 1.5 grams ofsodium cyano borohydride, whereupon the mixture was left standingovernight. The amino acid formed was esterified by addition of a mixtureof 200 milliliters of dry methanol and 20 milliliters of concentratedsulphuric acid and heating for 3 hours under reflux. The mixture waspoured into ice-water, aqueous ammonia added to alkaline reaction andextracted with ether. The ether-solution contained the methyl ester of1-(4-carboxycyclohexyl)-4-(2-trifluoromethyl-9-thioxanthenylidene)piperidineformed and was reduced after drying without further purification using1.5 grams of lithium aluminium hydride. The reaction mixture was workedup as described in Example 2, and 5.5 grams of1-(4-hydroxymethylcyclohexyl)-4-(2-trifluoromethyl-9-thioxanthenylidene)piperidinewere obtained by crystallization from ether as white crystals whichmelted at 193-197 degrees Centigrade.

EXAMPLE 8 1-(4-Hydroxycyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidineand its hydrochloride

In the same manner as described in Example 7 a mixture of 2.2 grams of4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine and 8.5grams of benzoyloxycyclohexanone in 30 milliliters of dry methanoladjusted to pH 5 were reduced with 1.5 grams of sodium cyanoborohydrideand the resulting 1-(4-benzoyloxycyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidinereduced with lithium aluminium hydride as described in Example 2.

8.4 Grams of the hydrochloride of1-(4-hydroxycyclohexyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidinewere obtained as white crystals which melted at 208-211 degreesCentigrade.

EXAMPLE 91-(Cis-2-hydroxymethylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidineand its oxalate

A mixture of 7.3 grams of4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine, 3.3 gramsof cis-hexahydrophthalic acid anhydride and 30 milliliters of toluenewas heated under reflux for 5 hours. After cooling 200 milliliters ofdry ether were added and the mixture reduced with 2 grams of lithiumaluminium hydride in the same manner as described in Example 2.

7.8 Grams of the oxalate of1-(cis-2-hydroxymethylcyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinewere obtained by drystallization from acetone as white crystals whichmelted at 155-156 degrees Centigrade.

EXAMPLE 10 The decanoic acid ester of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperidine

6 Grams of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperidinewere dissolved in 50 milliliters of dry pyridine. 4 Grams ofdecanoylchloride were added and the mixture left standing for 18 hoursat room temperature. The mixture was poured into 1 liter of water andextracted with 100 milliliters of isopropyl ether. The etherphase waswashed with water, dried over anhydrous potassium carbonate, filteredand evaporated to about 15 milliliters. By addition of petroleum etherand cooling 8 grams of the decanoic acid ester of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)-piperidinewere obtained as a white crystalline substance which melted at 100-108degrees Centigrade.

In the same manner was prepared:

The decanoic acid ester of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine.Melting point of the hydrochloride: 210-212 degrees Centigrade.

The palmitic acid ester of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-8-thioxanthenylidene)-piperidine.

The behenic acid ester of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)-piperidine.

EXAMPLE 111-(4-Oxocyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidineand its hydrochloride

A mixture of 13 grams of1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine,80 milliliters of cyclohexanone, 300 milliliters of dry toluene and 4grams of aluminiumisopropoxide was heated to boiling, and in the courseof one hour 200 milliliters of liquid were distilled off. The reactionmixture was cooled, water was added and the aluminium hydroxide whichprecipitated was sucked off. The organic layer was extracted with dilutehydrochloric acid, the acid solution made alkaline and extracted withether. The ether phase was dried over anhydrous potassium carbonate andevaporated, the residue was dissolved in acetone, and by addition of dryhydrogen chloride in ether the hydrochloride1-(4-oxocyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidinewas obtained as white crystals which melted at 232-235 degreesCentigrade. Yield: 4.5 grams.

EXAMPLE 121-(Trans-4-aminocyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperidineand its acetylderivative and mesylderivative

4-(2-Chloro-9-thioxanthenylidene)piperidine was reacted withtrans-4-(2,2,2-trichloroethoxycarbonylamino)cyclohexanecarbonyl chlorideas described in Example 2 (Method b).1-(Trans-4-(2,2,2-trichloroethoxycarbonylamine)cyclohexanecarbonyl)-4-(2-chloro-9-thioxanthenylidene)piperidinewas thereby obtained as a yellow oil.

The yellow oil was reduced with activated zink in acetic acid accordingto the procedure described for4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine inExample 1.1-(Trans-4-aminocyclohexylcarbonyl)-4-(2-chloro-9-thioxanthenylidene)piperidinewas thereby obtained as a white crystalline substance melting at 230-260degrees Centigrade after recrystallization from toluene.

This substance was then reduced with lithium aluminium hydride asdescribed in example using dry tetrahydrofuran instead of ether.1-(Trans-4-aminocyclohexylmethyl)-4-(2-chloro-9-thioxanthenylidene)piperidinewas thus obtained as a white crystalline substance melting at 128-135degrees Centigrade.

The starting material,trans-4-(2,2,2-trichloroethoxycarbonylamino)cyclohexanecarbonylchloride, was prepared from trans-4-aminocyclohexane carboxylic acid bya Schotten-Baumann reaction with the 2,2,2-trichloroethylester ofchloroformic acid followed by reflux for three hours with 50% excess ofthionyl chloride. It was obtained as a yellow oil.

In corresponding manner was prepared:

1-(Trans-4-aminocyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.MP: 100-102 degrees Centigrade.

The acetyl derivative of the last mentioned amine was prepared toconventional manner by treatment of the amine with acetic anhydride intoluene and melted at 215-217 degrees Centigrade.

The corresponding mesyl derivative was prepared by dissolving 6 grams ofthe amine in 50 milliliters of dichloromethane, adding a solution of 30grams of potassiumcarbonate in 100 milliliters of water, and, whilestirring vigorously, adding dropwise at zero degrees Centigrade 10 gramsof mesyl chloride. The organic phase was dried over anhydrous potassiumcarbonate and filtered.

By addition of ether 3 grams of the mesylderivative were obtained,melting at 170-180 degrees Centigrade.

The novel xanthones and thioxanthones used as starting materials for thepreparation of the compounds of Formula II were prepared as follows:

2-Methylthio-6-fluoro-9-thioxanthone 375 Grams of2-(p-methylthiophenylthio)-4-fluoro-benzoic acid(Collec.Czech.Chem.Commun. 40, pg. 3523 (1975)) were heated with 2.7kilograms of polyphosphoric acid while stirring for 3 hours at 140degrees Centigrade. The mixture was cooled to 110 degrees Centigrade andpoured into ice-water. The precipitate was sucked off, suspended inaqueous ammonia and sucked off again. After recrystallization frompyridine 200 grams of 2-methylthio-6-fluoro-9-thioxanthone was obtainedas a yellow crystalline substance which melted at 135-138 degreesCentigrade. 2-Methyl-6-fluoro-9-thioxanthone

A mixture of 110 grams of 2-bromo-4-fluoro-benzoic acid, 63 grams of4-methylthiophenol, 100 grams of potassium carbonate, 250 milliliters ofdimethylformamide, 2 grams of active copper and 1 gram of cuproiodidewas heated while stirring under reflux for 16 hours. The mixture waspoured into water, undissolved substance sucked off and the resultingsolution made acid with hydrochloric acid. The precipitate was suckedoff and dissolved in ether. The ether solution was dried over anhydrousmagnesium sulphate, treated with active carbon and most of the etherevaporated. By addition of petroleum ether and cooling 81 grams of2-(4-methylphenylthio)-4-fluorobenzoic acid were obtained as whitecrystals which melted at 190-200 degrees Centigrade.

This acid was heated at 50-60 degrees Centigrade with 650 millilitersconcentrated sulphuric acid while stirring, whereupon the mixture waspoured unto crushed ice. The precipitate was sucked off, suspended inaqueous ammonia and sucked off again. After recrystallization fromethanol 41 grams of 2-methyl-6-fluoro-9-thioxanthone were obtained aspale yellow crystals which melted at 159-165 degrees Centigrade.

2-Fluoro-6-methyl-9-thioxanthone

A mixture of 80 grams of 2-bromo-4-methylbenzonitrile, 52 grams of4-fluorothiophenol, 56 grams of potassium carbonate, 200 milliliters ofdimethylformamide and 1 grams of active copper was heated whilestirring. At 90 degrees Centigrade a reaction started resulting in riseof temperature and separation of potassium bromide. The mixture washeated under reflux for one hour, cooled and poured into water. Theprecipitate was sucked off and dissolved in ether. The ether solutionwas washed with dilute sodium hydroxide solution, dried over anhydrousmagnesium sulphate, treated with active carbon and the ether evaporated.The residue was recrystallized from ethanol, and 93 grams of2-(4-fluorophenylthio)-4-methylbenzonitrile were obtained as whitecrystals which melted at 93-96 degrees Centigrade.

This nitrile was heated under reflux for 16 hours with a solution of 85grams of potassium hydroxide in 600 milliliters of 80% ethanol. Themixture was poured into water and made acid with hydrochloric acid. 96Grams of 2-(4-fluorophenylthio)-4-methylbenzoic acid crystallizedthereby as a white crystalline substance which melted at 185-193 degreesCentigrade.

By treatment with concentrated sulphuric acid as described in theprevious example, 58 grams of 2-fluoro-6-methyl-9-thioxanthone wereobtained after recrystallization from ethanol as yellow crystals whichmelted at 166-170 degrees Centigrade.

2-Methoxy-6-fluoro-9-thioxanthone

This substance is prepared as described for2-methyl-6-fluoro-9-thioxanthene, and the intermediate2-(p-methoxyphenylthio)-4-fluoro-benzoic acid melts at 195-204 degreesCentigrade.

This substance yields by heating with polyphosphoric acid, as describedabove for 2-methylthio-6-fluoro-9-thioxanthone,2-methoxy-6-fluoro-9-thioxanthone, which melts at 170-174 degreesCentigrade.

2-Trifluoromethyl-6-methyl-9-thioxanthone

A mixture of 40 grams of sodium hydroxide, 1 liter of ethanol and 124grams of m-thiocresol was stirred until the sodium hydroxide wasdissolved.

206 Grams of 2-chloro-5-trifluoromethylbenzonitrile were then addedwhile stirring and under reflux. The mixture was then heated underreflux for two hours. After cooling 100 grams of potassium hydroxidewere added and the mixture heated under reflux overnight. The mixturewas then diluted with 3 liters of water and made acid with hydrochloricacid. The precipitate was filtered off and consisted of2-(3-methylphenylthio)-5-trifluoromethylbenzoic acid. Yield: 240 grams.

This was then treated with sulphuric acid as described for2-methyl-6-fluoro-9-thioxanthone. The resulting substance consistedmainly of 2-trifluoro-6-methyl-9-thioxanthone with some2-trifluoromethyl-8-methyl-9-thioxanthone. When boiling this mixturewith acetone the more soluble 8-methyl-compound will go into solution.The remaining 2-trifluoromethyl-6-methyl-9-thioxanthone was obtained asa yellow crystalline substance, which melts at 174-178 degreesCentrigrade. Yield: 80 grams.

2-Methylthio-6-fluoro-9-xanthone

A mixture of 36.8 grams of 5-methylthio salicylic acid, 38 grams of3-bromofluorobenzene, 32 grams of anhydrous potassium carbonate and 3grams of copper powder in 100 milliliters of dimethylformamide washeated to boiling, and 25 milliliters of liquid were distilled off untilthe temperature in the mixture reached 150 degrees Centigrade. 35 Gramsof 3-bromofluorobenzene were then added, and the mixture was refluxedovernight. 200 Milliliters of water were added, and the warm reactionmixture was filtered with charcoal. The filtrate was extracted once withdiethylether and made acid with 6 N hydrochloric acid. The precipitatewas sucked off and taken up in 500 milliliters of diethylether, driedover anhydrous magnesium sulphate and concentrated. The crystals weresucked off and dried. 26 Grams of2-(3-fluoro-phenoxy)-5-methylthio-benzoic acid melting at 137-140degrees Centigrade were obtained.

The 26 grams of this acid were added to 225 grams of polyphosphoric acidwhile stirring and the mixture heated on a steam bath for three hours.The reaction mixture was poured onto ice, filtered and taken up in 250milliliters of methylene chloride. The organic phase was washed with 25%aqueous ammonia and water, dried over anhydrous magnesium sulphate andevaporated to give 20 grams of a mixture of 6- and8-fluoro-2-methylthio-9-xanthones.

Three recrystallizations from 16 milliliters of pyridine yielded 6 gramsof pure 2-methylthio-6-fluoro-9-xanthone which melted at 113-116 degreesCentigrade.

The pharmacological testing of the novel xanthones and thioxanthenes ofFormula I consisted of standard and reliable tests.

There the results with salts were compared with the results obtainedwith the free base it was found that the effect was the same as thatobtained with the equivalent amount of free base.

The tests may be described as follows:

Methylphenidate antagonism (ED50 mg/kg i.p.)

Perspex observation cages without bottom and lid, consisting of 5sections each measuring 12×25×30 cm. White corrugated paper. Mice, male,18-25 g.

Dosage and procedure

The test substance is given i.p. in the doses 0, 1/8, 1/32 and 1/128 ofthe determined "i.p. LD50". 3×2 mice are used for each dose level. Twoor 24 hours after injection of test substance, methylphenidate, 60mg/kg, is injected s.c. After administration of methylphenidate the miceare placed in the observation cages, 2 in each cage, where they remainfor exactly 1 hour. The cages are placed on corrugated paper, thecorrugations facing upwards. It is examined whether the mice have beenbiting the corrugated paper or not. If not, the substance has had anantagonistic effect. If one or more of the control pairs have not beenbiting, the test has to be repeated on a new set of mice.

The result is stated in fractions: 0/3, 1/3, 2/3, and 3/3 where 0, 1, 2and 3 are the number of pairs which have not been biting on receipt ofthe dose in question.

The results are calculated as the dose (ED₅₀), which causes antagonismin 50% of the test animals.

Amphetamine antagonism (ED₅₀ mg/kg i.p.)

Perspex observation cages without bottom and lid, consisting of 5sections each measuring 12×25×30 cm. White corrugated paper. Rats, male,230-270 g.

Dosage and procedure

The test substance is given i.p. in a reasonable dose based on thedetermined LD₅₀. Two or 24 hours later an intravenous injection ofamphetamine sulphate 13.6 mg/kg (10 mg/kg amphetamine base) is given,after which the rats are placed individually in the cages. The cages areplaced on white corrugated paper. Five rats are used for each doselevel. Observations are made after 55 minutes and 65minutes--observation time: 1 minute. The animals are observed forstereotypy (movements of the head, compulsive gnawing). If no stereotypyis demonstrated the substance has had an antagonistic effect. If thecompound has full antagonistic effect another group of rats is used at alower dose. If the compound shows no effect a higher dose is used. Theresults is stated as fractions: 0/5, 1/5, 2/5, 3/5, 4/5 and 5/5, where0, 1, 2, 3, 4 and 5 indicate the number of rats which have not shownstereotypy at the dose in question. The results are calculated as ED₅₀in mg/kg.

Catalepsy wire mesh, rat, max. (ED₅₀ mg/kg s.c.)

A vertical wire netting (50 cm×49 cm). The meshes (openings) of thenetting are square (1 cm×1 cm). The wire diameter is 2 mm. Stop watch.Rats, male, 180-200 g.

Dosage and procedure

The animals are labeled and used in groups of five. The test substanceis injected subcutaneously (s.c.) (5 ml/kg) at 4 dose levels selectedfrom the fixed dose scale.

The animals are placed in the middle of the vertical wire netting 60,120, 180, 240, 300 and 360 minutes after injection of the test compound.The animals are considered cataleptic when they remain immobile during aperiod of 15 seconds. This cataleptic reaction is designated +. If therats are "atonic" and passively slide down the wire mesh they areconsidered not cataleptic. If the animals climb up and down the wiremesh they are nor cataleptic. In both situations the designation--isused.

The results are recorded in fractions: 0/5, 1/5, 2/5, 3/5, 4/5 and 5/5,where 0, 1, 2, 3, 4 and 5 are the number of rats with designation+at thetime where the dose in question possessed the strongest effect withinthe first 6 hours.

The compounds tested will appear from the following table:

                                      TABLE 1                                     __________________________________________________________________________    Code Number                                                                           X       Y  n R               Z                                        __________________________________________________________________________    Lu 14-047                                                                             2-Cl    H  1                                                                                ##STR17##      S                                        Lu 15-014                                                                             2-Cl    H  1                                                                                ##STR18##      S                                        Lu 14-106                                                                             2-Cl    H  2                                                                                ##STR19##      S                                        Lu 14-140                                                                             2-Cl    H  1                                                                                ##STR20##      S                                        Lu 15-041                                                                             2-Cl    H  1                                                                                ##STR21##      S                                        Lu 13-135                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR22##      S                                        Lu 15-013                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR23##      S                                        Lu 15-030                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR24##      S                                        Lu 15-048                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR25##      S                                        Lu 15-038                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR26##      S                                        Lu 15-052                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR27##      S                                        Lu 14-130                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR28##      S                                        Lu 15-131                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR29##      S                                        Lu 14-116                                                                             2-SCH.sub.3                                                                           F  1                                                                                ##STR30##      S                                        Lu 15-019                                                                             2-SCH.sub.3                                                                           H  1                                                                                ##STR31##      S                                        Lu 14-114                                                                             2-Cl    F  1                                                                                ##STR32##      S                                        Lu 14-117                                                                             2-Cl    F  2                                                                                ##STR33##      S                                        Lu 15-070                                                                             2-Cl    F  1                                                                                ##STR34##      S                                        Lu 15-062                                                                             3-F     F  1                                                                                ##STR35##      S                                        Lu 14-062                                                                             2-F     CH.sub.3                                                                         2                                                                                ##STR36##      S                                        Lu 14-090                                                                             2-F     CH.sub.3                                                                         1                                                                                ##STR37##      S                                        Lu 14-070                                                                             2-CH.sub.3                                                                            F  2                                                                                ##STR38##      S                                        Lu 14-082                                                                             2-CH.sub.3                                                                            F  1                                                                                ##STR39##      S                                        Lu 16-107                                                                             2-SO.sub.2 N(CH.sub.3).sub.2                                                          F  1                                                                                ##STR40##      S                                        Lu 16-066                                                                             2-SO.sub.2 CH.sub.3                                                                   H  1                                                                                ##STR41##      S                                        Lu 16-052                                                                             2-OCH.sub.3                                                                           F  1                                                                                ##STR42##      S                                        Lu 16-014                                                                             2-CF.sub.3                                                                            CH.sub.3                                                                         1                                                                                ##STR43##      S                                        Lu 15-121                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR44##      S                                        Lu 16-105                                                                             2-Cl    H  2                                                                                ##STR45##      S                                        Lu 16-104                                                                             2-CF.sub.3                                                                            F  2                                                                                ##STR46##      S                                        Lu 15-089                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR47##      S                                        Lu 15-119                                                                             2-SCH.sub.3                                                                           F  1                                                                                ##STR48##      O                                        Lu 16-088                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR49##      S                                        Lu 16-042                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR50##      S                                        Lu 16-081                                                                             2-Cl    H  1                                                                                ##STR51##      S                                        Lu 16-043                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR52##      S                                        Lu 16-049                                                                             2-CF.sub.3                                                                            F  1                                                                                ##STR53##      S                                        __________________________________________________________________________

As reference substances were used the following neuroleptic drugsdesignated by their INN-names (International Nonproprietary Names):flupentixol, clopenthixol, chlorprothixene, fluphenazine,chlorpromazine, haloperidol and clozapine. Moreover the cis- (z)-isomerof2-trifluoromethyl-6-fluoro-9-(3-(4-(2-hydroxyethyl)-1-piperidyl)propylidene)-thioxanthene;INN-name; piflutixol.

                                      TABLE 2                                     __________________________________________________________________________            Methylphenidate antagon                                                                    Amphetamine  Remarks                                     Substance                                                                             2 h    24 h  antagon                                                                              Catalepsy                                                                           Duration                                    __________________________________________________________________________    Lu 14-047                                                                             0.59   >20   0.32   3.5   short acting, strong                        Lu 15-014                                                                             0.20   >10          2.5    "                                          Lu 14-106                                                                             0.51   >40   1.0    6.6    "                                          Lu 14-140                                                                             0.77   >40                 "                                          Lu 15-041                                                                             0.62   3.6   <0.31        moderately long acting, strong              Lu 13-135                                                                             0.32   0.19  0.32   0.4   very long acting, strong                    Lu 15-013                                                                             0.63   0.10  0.76   1.2   long acting, strong                         Lu 15-030                                                                             0.28   0.05  0.88   0.39  long acting, very strong                    Lu 15-048                                                                             1.30   0.13  <0.31        long acting, strong                         Lu 15-138                                                                             1.30   0.15  1.7           "                                          Lu 15-052                                                                             0.32   0.06  0.9    0.026  "                                          Lu 14-130                                                                             0.77   0.70  0.62   2.8   long acting, moderately strong              Lu 15-031                                                                             0.52   0.55  1.3           "                                          Lu 14-116                                                                             0.44   0.38  0.28   0.58  long acting, strong                         Lu 15-019                                                                             0.77   >40   0.59   0.60  short acting, moderately strong             Lu 14-114                                                                             0.1    6.6   0.35         short acting, strong                        Lu 14-117                                                                             0.21   29    0.34   1.0    "                                          Lu 15-070                                                                             0.51   0.5                moderately long acting, moderately                                            strong                                      Lu 15-062                                                                             0.77   >10   0.85         short acting, moderately strong             Lu 14-062                                                                             0.51   >40                 "                                          Lu 14-090                                                                             1.25   32                  "                                          Lu 14-070                                                                             0.32   >40   1.3    1.8    "                                          Lu 14-082                                                                             0.79   >10                 "                                          Lu 16-107                                                                             1.9    0.76         0.28  long acting, moderately strong              Lu 16-066                                                                             0.73   >10          0.25  short acting, moderately strong             Lu 16-052                                                                             0.31   29    0.56   0.23   "                                          Lu 16-014                                                                             0.31   1.9   1.0    0.97  long acting moderately strong               Lu 15-121                                                                             2.2    0.31  10.0   >10   long acting, strong, weak catalep.          Lu 16-105                                                                             0.16   28    1.2    0.38  short acting, strong                        Lu 16-104                                                                             0.06   1.5   0.15   0.11  relatively short acting, strong             Lu 15-089                                                                             0.32   0.32  1.8    2.7   relatively short acting, moderately                                           strong                                      Lu 15-119                                                                             0.09   0.11  0.56   0.08  very strong, long acting.                   Lu 16-088                                                                             0.77   0.06  0.30 p.o.                                                                            0.81  strong, long acting                         Lu 16-042                                                                             1.2    0.17  2.5 p.o.                                                                             3.3    "                                          Lu 16-081                                                                             0.5    ˜10          moderately strong, short acting.            Lu 16-043                                                                             >10    0.42         >20   relatively strong, long acting              Lu 16-049                                                                             1.0    0.49  2.5 p.o.                                                                             1.7 p.o.                                                                            moderately strong, long acting.             flupentixol                                                                           0.20   >20   0.69   0.25  short acting, strong                        clopenthixol                                                                          1.20         0.77   0.95  short acting, moderately strong             chlorprothixene                                                                       0.71   >20   6.1    4.0    "                                          fluphenazine                                                                          0.04   3.6   0.08   0.099 short acting, very strong                   chlorpromazine                                                                        4.0    20    7.1    5.6   short acting, moderately strong             haloperidol                                                                           0.06         0.14   0.21  short acting, very strong                   clozapine                                                                             >160         >40    85    short acting, weak                          piflutixol                                                                            0.03   0.03         0.05  48-72h LD.sub.50 p.o. in male rats                                            after                                                                         1 week 1.5mg/kg                             __________________________________________________________________________

From Table 2 it appears that among the compounds having a substituent inthe 2-position and a fluorine atom or methyl group at position 6 onefinds the most long acting and also strongest acting.

On the other hand, they also show a comparatively high catalepticactivity, which indicates extrapyrimidal symptoms. The compounds whereinY is hydrogen are as general rule rather short acting but, on the otherhand, they often show a more favourable ration between the catalepticactivity and the methylphenidate antagonism.

Among the compounds wherein R is a cyclohexyl group having from one tothree hydroxyl groups one finds some of the most promising compounds.Especially remarkable are Lu 13-135, Lu 15-030, Lu 15-052 and Lu 15-119in that they are very strong and long acting but they also have acataleptic activity. Interesting is Lu 15-121 in that it seems to bestrong, long acting and at the same time having no cataleptic activity.

When comparing the most long acting and strongest of the compounds ofFormula I with piflutixol, which is the most patent and at the same timethe most long acting neuroleptic so far known, it has been found thatthey cause much less sedation. Moreover, they have much strongeranticholinergic effects than the compounds known from U.S. Pat. No.4,042,695, and this is considered an indication of a lower degree ofundesired extrapyrimidal side effects.

The acute toxicity, as measured by LD₅₀ in male rats following peroraladministration, is much lower for Lu 13-135 when compared withpiflutixol one week after administration. The figure for Lu 13-135 is >60 mg/kg against 1.5 mg/kg for piflutixol. The considerably greatertoxicity of piflutixol being attributed mainly to the aforementionedvery strong sedative effects.

The compounds of Formula I and the non-toxic acid addition salts thereofmay be administered to animals such as dogs, cats, horses sheeps or thelike, including human beings, both orally and parenterally, and may beused for example in the form of tablets, capsules, powders, syrups or inthe form of the usual sterile solutions for injection. Results uponadministration to human beings have been very gratifying.

Most conveniently the compounds of Formula I are administered orally inunit dosage form such as tablets or capsules, each dosage unitcontaining a non-toxic acid addition salt of one of the said compoundsin an amount of from about 0.05 to about 50 mg, most preferably,however, from about 1 to 10 mg, calculated as the free amine, the totaldaily dosage usually ranging from about 0.5 to about 300 mg. The exactindividual dosages as well as daily dosages in a particular case will,of course, be determined according to established medical principlesunder the direction of a physician.

When preparing tablets, the active ingredient is for the most part mixedwith ordinary tablet adjuvants such as corn starch, potato starch,talcum, magnesium stearate, gelatine, lactose, gums, or the like.

When the compound of Formula I is an ester, perferably a decanoic acidester, palmitic acid ester or a behenic acid ester, the composition mayadvantageously be an oily solution for injection, and such solutionsoften have a very prolonged effect when compared with the correspondingunesterified compound.

Typical examples of formulas for composition containing1-(trans-4-hydroxycyclohexylmethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenyliden)-piperidine(called Lu 13-135 for short) as the active ingredient are as follows:

(1) Tablets containing 0.1 milligram of Lu 13-135 calculated as the freebase:

Lu 13-135: 0.1 mg

lactose: 37 mg

potato starch: 74 mg

gelatine: 2 mg

talcum: 8 mg

(2) Solution for injection containing per ml:

Lu 13-135: 0.2 mg

sodium chloride: 9.0 mg

sterile water ad: 1 ml

(3) Syrup containing per milliliter:

Lu 13-135: 0.2 mg

methyl-paraben: 1.0 mg

propyl-paraben: 0.1 mg

saccharose: 400 mg

water: ad: 1 ml

(4) Capsules containing per capsule:

Lu 13-135: 1 mg

lactose: 40 mg

magnesium stearate: 0.5 mg

Any other pharmaceutical tableting adjuvants may be used provided thatthey are compatible with the active ingredient, and additionalcompositions and dosage forms may be similar to those presently used forneuroleptics, such as thiothixene, clopenthixol or flupenthixol. Alsocombinations of the compounds of Formula I as well as their non-toxicacid salts with other active ingredients, especially other neuroleptics,thymoleptics, tranquilizers or the like, fall within the scope of thepresent invention.

As previously stated, when isolating the compounds of Formula I in theform of an acid addition salt the acid is preferably selected so as tocontain an anion which is non-toxic and pharmacologically acceptable, atleast in usual therapeutic doses. Representative salts which areincluded in this preferred group are the hydrochlorides, hydrobromides,sulphates, acetates, phosphates, nitrates, methanesulphonates,ethane-sulphonates, lactates, citrates, tartrates or bitartrates,embonates and maleates of the amines of Formula I. Other acids arelikewise suitable and may be employed if desired. For example; fumaric,benzoic, ascorbic, succinic, salicylic, bismethylenesalicylic,propionic, gluconic, malic, malonic, mandelic, cannamic, citraconic,stearic, palmitic, itaconic, glycolic, benzenesulphonic, and sulphamicacids may also be employed as acid addition saltforming acids.

When it is desired to isolate a compound of the invention in the form ofthe free base, this may be done according to conventional procedure asby dissolving the isolated or unisolated salt in the water, treatingwith a suitable alkaline material, extracting the liberated free basewith a suitable organic solvent drying the extract and evaporating todryness or fractionally distilling to effect isolation of the free basicamine.

The invention also comprises a method for the alleviation, palliation,mitigation or inhibition of the manifestations of certainphysiological-psychological abnormalies of animals by administering to aliving animal body, including human beings, an adequate quantity of acompound of Formula I or a non-toxic acid addition salt thereof. Anadequate quantity would be from about 0.001 mg to about 1 mg per kg ofbody weight in each unit dosage, and from about 0.003 milligrams toabout 3 milligrams/kg of body weight per day.

It is to be understood that the invention is not limited to the exactdetails of operation or exact compound or compositions shown anddescribed, as obvious medifications and equivalents will be apparent toone skilled in the art.

We claim:
 1. A compound of the formula: ##STR54## wherein X₁, Y, Z, mand R₁ are defined as follows: X₁ is a halogen atom, an alkyl group withone to four carbon atoms inclusive, an alkoxy group with one to fourcarbon atoms inclusive, a methylmercapto group, or a trifluoromethylgroup;Y is hydrogen, fluorine, or a methyl group; Z is oxygen orsulphur; m is zero or an integer from one to two, inclusive; and R₁ is acycloalkyl group with four to six carbon atoms inclusive in the ring,which is substituted with one to four substituents selected from thegroup consisting of: amino; acetamino; mesylamino; and protectedhydroxy- or protected hydroxymethyl, any such protected hydroxy orhydroxymethyl group present being protected by esterification into anester of an aliphatic carboxylic acid having ten to twenty-two carbonatoms inclusive; and, when a previously-named substituent is present,also methyl.
 2. A compound of the formula: ##STR55## wherein X₁, Y, Z, mand R₁ are defined as follows: X₁ is a halogen atom, an alkyl group withone to four carbon atoms inclusive, an alkoxy group with one to fourcarbon atoms inclusive, a methylmercapto group, or a trifluoromethylgroup;Y is hydrogen, fluorine, or a methyl group; Z is oxygen orsulphur; m is zero or an integer from one to two, inclusive; and R₁ is acycloalkyl group with four to six carbon atoms inclusive in the ring,which is substituted with one to four substituents selected from thegroup consising of: amino; acetamino; and mesylamino; protected hydroxy-or protected hydroxymethyl and, when a previously-named substituent ispresent, also methyl; a five- or six-membered saturated heterocyclicring having one or two hetero-atoms selected from oxygen and nitrogenatoms and being optionally substituted with a protected hydroxy group;any such protected hydroxy or hydroxymethyl group present beingprotected by esterification into an ester of an aliphatic carboxylicacid having ten to twenty-two carbon atoms inclusive.
 3. A compound ofclaim 1 which is1-(Trans-4-acetoxycyclohexanecarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine.